Prognostic evaluation of specific cutaneous infiltrates in B-chronic lymphocytic leukemia

The relationship between numerous histologic variables and survival was investigated in 54 consecutive lesions of specific skin infiltrates of B-cell chronic lymphocytic leukemia (B-CLL) from 27 patients (16 males and 11 females, mean age 65 years, range 42-83 years). All patients were followed for up to 204 months or until death. Histopathologically, the infiltrates showed a patchy perivascular (35%), diffuse (31.5%), nodular (31.5%) or bandlike (1.9%) pattern. In 28% of the cases, an admixture of reactive cells within the infiltrate including eosinophils, histiocytes, neutrophils and plasma cells was observed. Cytomorphologically, small B-lymphocytes with condensed chromatin predominated in most infiltrates. However, some biopsies showed a small but significant number of medium- or large-sized neoplastic cells of the B-lymphocyte lineage with variable cytomorphological features. In a multivariate analysis, several histologic parameters within the infiltrates were found to show a significant association with long survival, namely, an infiltrate of moderate density, a nodular pattern, involvement of the lower dermis only, and presence of predominantly small B-lymphocytes (more than 95%) with condensed chromatin. Histologic variables that independently correlated with relatively short survival included an infiltrate of severe intensity, a diffuse pattern, epidermal changes (especially acanthosis and ulceration), medium-sized and large B-lymphocyte (more than 5%), and reactive cells within the infiltrate (neutrophils, eosinophils, and plasma cells). Overall analysis of our results showed two histologic patterns with a significant prognostic impact (p < 0.01; z = 5.4). Pattern I (33 biopsies) correlated with relatively long survival (2-year survival rate; 97%) and consisted of infiltrates showing predominantly small B-lymphocytes (more than 95%) without reactive cells or epidermal changes. Pattern II (21 biopsies) indicated short survival (2-year survival rate; 49%) and included all the rest of the biopsies i.e., infiltrates with medium- and large-sized B-lymphocytes (more than 5%), admixture of reactive cells, and epidermal changes. Results from our study suggest that histologic features in specific skin infiltrates of B-chronic lymphocytic leukemia may be helpful in identifying prognostically different subgroups of patients and planning therapeutic schedules.     

Respiratory symptoms and lung function in aborigines from tropical Western Australia

To estimate the prevalence of respiratory symptoms, bronchial hyperresponsiveness, smoking, and atopy in a population of Australians of Aboriginal descent (AAD), to determine the association of these and other factors with lung function, and to compare levels of lung function of AAD with Australians of European descent (AED) according to age and height, and to explore reasons for their differences, we conducted a study of 96 male (41 of whom were under 18 yr of age) and 111 female (48 of whom were under 18 yr of age) AAD living in a single remote tropical community in 1993. This population provided data on age, height, and lung function. A modified British Medical Research Council (MRC) questionnaire on respiratory symptoms and smoking was administered. FEV1, FVC, height, age, and bronchial responsiveness to inhaled methacholine were measured. Atopic status was assessed by skin prick tests for eight common allergens. Age- and sex-adjusted lung function was similar to that of other AAD groups and lower than in AED. For children, lung function increased less with increasing height in AAD than in AED. Lung function was reduced in adult AAD as compared with adult AED, although it was not possible to determine statistically whether lung function started to decline at an earlier age or declined faster with increasing age in AAD. A history of asthma, smoking, dyspnea, cough, or sputum production; atopic status; and increased bronchial responsiveness were all associated with lower levels of lung function. Differences in lung function between AAD and AED appear to be determined by characteristics that may be inherited, as well as by adverse external influences.     

Respiratory symptoms and lung function abnormalities among machine operators in automobile production

This cross-sectional study was designed to assess differences in prevalence of respiratory symptoms and lung function between machine operators exposed to semisynthetic or soluble metal-working fluids (MWFs) and unexposed assemblers and to assess exposure-response relationships with MWF type, total aerosol, endotoxin, culturable bacteria and fungi. We evaluated 183 machine operators and 66 assemblers from one large automobile transmission plant using questionnaires, spirometry data, and cross-shift assessment of both lung function and respiratory symptoms. We found that airborne exposures to total aerosol, endotoxin, culturable bacteria and fungi were higher in machine operations than in the assembly area. There was a correlation between bulk and airborne culturable bacteria, but not between bulk and airborne culturable fungi. Machine operators had significantly more usual cough, usual phlegm, work-related chest tightness and post-shift symptoms of chest tightness, throat irritation, and cough compared with assemblers. We found exposure-response relationships between respiratory symptoms and total aerosol, as well as culturable fungi and bacteria. Associations with endotoxin were not strong or consistent, possibly because airborne levels were generally low. Cross-shift lung function decrements did not differ between machine operators and assemblers and there were no associations with MWF or specific exposures. The finding of respiratory symptoms at low levels of exposure in this study suggests the need to re-assess total aerosol thresholds. Associations between airborne fungal exposures and respiratory symptoms need further study to characterize sources of exposure other than MWF in machining operations.     

Respiratory function tests in pediatric practice

To evaluate the role of tumour necrosis factor (TNF) in gut-derived sepsis, mice were given Pseudomomas aeruginosa strain D4 by bacterial suspension in their drinking water during which time ampicillin (200 mg/kg) was given to disrupt the normal indigenous bacterial flora. Cyclophosphamide was additionally administered to induce bacterial translocation of the P. aeruginosa that had colonized the gastrointestinal tract, and thereby to cause gut-derived sepsis. In this model, TNF-alpha was detected in serum from the next day after the second cyclophosphamide administration, increasing to level of 3 ng/ml in lethal conditions. Average serum TNF-alpha level was significantly higher in mice with bacteraemia than in those without bacteraemia. Treatment with 0.8 microg/kg of recombinant human TNF-alpha (rhTNF-alpha) did not affect the mortality, whereas administration of either 4 and 20 microg/kg of rhTNF-alpha significantly increased the mortality rate in comparison with saline-treated mice. Bacterial counts in liver and blood were significantly higher in 20 microg/kg of rhTNF-alpha treated mice than in saline-treated mice. Treatment with murine anti-TNF-alpha monoclonal antibody significantly reduced the mortality from septic infection. We conclude that TNF-alpha may facilitate bacterial translocation and causes deterioration of gut-derived sepsis due to P. aeruginosa in mice.     

Induction of "in vitro" apoptosis by fludarabine in freshly isolated B-chronic lymphocytic leukemia cells

The cytotoxic effects and apoptosis (programmed cell death) induced by fludarabine (FLU), interleukin-2 (IL-2), interleukin-4 (IL-4), IL-2 plus IL-4, alpha-interferon (alpha-IFN), and mafosfamide were evaluated "in vitro" on freshly isolated B-cell chronic lymphocytic leukemia (B-CLL) cells. Cytotoxicity was evaluated according to the soluble tetrazolium/formazan assay. Treatment with mafosfamide, fludarabine, and IL-4 resulted in significant anti-tumor activity against all the freshly isolated samples. On the other hand, no significant cytotoxic activity was observed with alpha-IFN, IL-2, and the combination of IL-2 and IL-4. Apoptosis was evaluated by electrophoresis gel of DNA oligonucleosomal fragments and only FLU significantly activated apoptosis in all the samples. It appears that fludarabine is active against B-CLL cells acting by an direct cytotoxic effect and/or the induction of cell death by apoptosis.     

Induced sputum, bronchoalveolar lavage and blood from mild asthmatics: inflammatory cells, lymphocyte subsets and soluble markers compared

Airway inflammation in asthma can be measured directly by invasive bronchoalveolar lavage (BAL), directly and relatively noninvasively by induced sputum and indirectly from peripheral blood. We compared cellular and fluid phase indices of inflammation in induced sputum, BAL and blood from 11 adults with mild stable asthma. On one day, induced sputum selected from saliva was collected and on the next, blood and BAL. Median results of sputum compared with BAL showed a higher number of nonsquamous cells (53 versus 0.8 x 10(6) cells x mL(-1), p=0.003), more neutrophils (34.3 versus 1.0%, p<0.001), CD4+ and CD19+ T-cells (76.5 versus 54.7%, p=0.01 and 5.2 versus 1.1%, p=0.03, respectively), fewer macrophages (603 versus 95.0%, p=0.002) and markedly higher levels of eosinophil cationic protein (ECP) (264 versus 2.0 microg x L(-1), p<0.001), tryptase (17.6 versus 2.2 UI x L(-1), p<0.001) and fibrinogen (1,400 versus 150 microg x L(-1), p=0.001). Sputum and BAL neutrophils and CD4+ T-cells were strongly correlated. Sputum and BAL differed from blood by having higher proportions of T-cells (94.9 and 98.9% versus 87.7%, p=0.002) and lower proportions of CD19+ T-lymphocytes (p=0.04 and 0.006). Sputum also differed from blood by having higher proportions of CD4+ T-cells (76.5 versus 51.4%, p=0.001), lower proportions of CD8+ cells (24.0 versus 403%, p=0.04) and a higher CD4+/CD8+ ratio (3.3 versus 1.4, p=0.01). We conclude that in mild asthmatics, sputum, bronchoalveolar lavage and blood measure different compartments of inflammation. Induced selected sputum has the advantage over bronchoalveolar lavage of higher density of cell recovery and stronger signal for fluid-phase markers.     

Antigen-specific immunoglobulin-A prevents increased airway responsiveness and lung eosinophilia after airway challenge in sensitized mice

The aim of this study was to examine the role of dopamine neurotransmission in the effects of morphine in the learned helplessness paradigm in rats, a generally recognized model of depression. In this model, rats first exposed to inescapable shocks (stressed rats) exhibited an escape deficit in a subsequent shuttle-box test performed 48 h later for 3 consecutive days. The numbers of escape failures and intertrial crossings (motor activity during each intertrial interval) were recorded. Morphine was injected twice daily for 5 days (6 mg/kg/day, s.c.), and haloperidol, a preferential D2-dopamine receptor antagonist, was injected i.p. 15 min before each shuttle-box session. At the highest dose tested (150 microg/kg) haloperidol mimicked the behavioral deficit produced by inescapable shocks. A 37.5 microg/kg dose of haloperidol, which was ineffective by itself, reversed the morphine-induced improvement of escape behavior in previously stressed rats and the morphine-induced increase in intertrial activity in both stressed and nonstressed animals. These results support roles (a) for a dysregulation of dopaminergic neuronal activity in the expression of escape deficit subsequent to an inescapable aversive situation, and (b) for a dopaminergic mediation in the effects of morphine in the learned helplessness paradigm.     

Respiratory function tests in the newborn and the infant

AIM: To study the mechanisms of the resistance to harringtonine (Har) in the HL60 cells. METHODS: Growth inhibition, karyotype analysis, flow cytometry, Western blotting and polymerase chain reaction. RESULTS: The Har-resistant HL60 cell line, named HR20, showed cross resistance to homoharringtonine, doxorubicin, daunorubicin, vincristine, and colchicine. The growth doubling time and the cell numbers in G1 phase were increased. The accumulation of cellular daunorubicin in the resistant cells was obviously reduced, but distinctly increased by tetrandrine and verapamil. The numbers of telocentromeric chromosome increased and the chromosomal aberration more occured in the resistant cells. The resistant cells overexpressed multidrug resistant mdr-1 gene and P-glycoprotein 150 kDa. CONCLUSION: The Har-resistant HL60 cell strain belonged to a multidrug resistance strain, overexpressing mdr-1 gene and P-glycoprotein.     

Interleukin-15 + thioredoxin induce DNA synthesis in B-chronic lymphocytic leukemia cells but not in normal B cells

We have previously shown that Staphylococcus aureus Cowan strain 1 particles (SAC) + thioredoxin (Trx) + IL-2 may induce B-chronic lymphocytic leukemia (B-CLL) cells to proliferate. In this paper we have examined IL-15, which has activities similar to IL-2, for its ability to stimulate B-CLL cells and compared its activity with that of IL-2. We found that B-CLL cells could be induced to DNA synthesis upon treatment with IL-15 + Trx. The presence of Trx was essential for the IL-15-induced DNA synthesis. This contrasts to the effect of IL-15 + Trx on normal CD5+ and CD5- B cells, where IL-15 + Trx alone only induced limited DNA synthesis. IL-15 was as effective in the induction of DNA synthesis in B-CLL cells as IL-2, but about 100-fold less potent with an EC50 of 200 ng/ml. In addition we found that the IL-15 + Trx-induced proliferation was inhibited by CD40 stimulation. We conclude that IL-15 together with a proper costimulus can induce B-CLL cells to proliferate in vitro.     

The effect of salmeterol on nocturnal symptoms, airway function, and inflammation in asthma

STUDY OBJECTIVE: To determine the efficacy of salmeterol alone in a group of patients with moderate asthma with nocturnal worsening of symptoms. DESIGN: Double-blind, randomized, placebo-controlled crossover study. SETTING: Tertiary care hospital specializing in respiratory diseases. PARTICIPANTS: Ten patients with nocturnal asthma. INTERVENTIONS: Subjects were randomized to salmeterol, 100 micrograms twice daily, or placebo for 6 weeks with a 1-week washout between treatment periods. Symptoms, nocturnal awakenings, and beta 2-agonist use were recorded daily. Spirometry was performed at weeks 1 and 6 of each period at bedtime and at 4 AM, and methacholine challenge was performed at 4 AM followed by bronchoscopy with BAL. BAL fluid analysis included cell count and differential count, eosinophil cationic protein, Charcot-Leyden crystal protein, leukotriene B4, and thromboxane B2. RESULTS: The percentage of nights with awakenings decreased significantly with salmeterol (69.8 +/- 8.7% vs 30.6 +/- 10.8% for placebo and salmeterol, respectively; p = 0.02). The percentage of 24-h days with supplemental inhaled beta 2-agonist use significantly decreased with salmeterol (85.9 +/- 9.4% vs 70.4 +/- 10.1% for placebo and salmeterol, respectively; p = 0.04). There were no significant differences in bronchial reactivity, 4 AM FEV1, overnight percentage change in FEV1, or indexes of airway inflammation. CONCLUSIONS: Salmeterol alone improves the number of nocturnal awakenings and supplemental 24-h beta 2-agonist use in nocturnal asthma without significantly altering lung function and airway inflammation.     

Respiratory health hazards and lung function in wildland firefighters

The authors discuss the multitude of contaminants to which wildland firefighters are exposed, including carbon monoxide, sulfur dioxide, particulate and silica, polyaromatic hydrocarbons, aldehydes, and benzene. They examine the respiratory effects of these contaminants and then present their recommendations for an occupational health program for wildland firefighters.     

Respiratory function and surgical reduction of lung volume

Emphysema is characterised by an enlargement of the terminal air spaces. Destructions of alveolar walls lead to a loss of the lung elastic recoil. The driving pressure for expiration is decreased and the outward forces acting on the bronchioles are lost, leading to bronchiolar collapse and airflow limitation. Hyperinflation of the lungs and overdistension of the chest wall cause the respiratory muscles to operate in unfavourable conditions. Patients with advanced emphysema have decreased quality of live: they are dyspneic at rest and are unable to perform exercise. Surgical excision of parts of diffusely emphysematous lungs (Lung Volume Reduction Surgery, LVRS) has been proposed since many years. Expansion of the remaining lung should increase lung elastic recoil and restore the outward forces on the bronchioles. It has been demonstrated that LVRS reduces dyspnea symptoms, improves exercise tolerance and enhances the quality of live. LVRS increases lung elastic recoil, airway conductance and maximal expiratory flow, reduces dynamic hyperinflation and improves the efficiency of the respiratory muscles. These improvements are maintained for at least 12 to 18 months. Preoperative evaluation, surgical-induced modifications of pulmonary functions and postoperative exercise training are exposed.     

Dissociation of airway responsiveness and bronchoalveolar lavage (BAL) cell composition in sensitized guinea-pigs after daily inhalation of ovalbumin

The association between inflammatory cell influx, cell activation status and change of airway responsiveness to acetylcholine (ACh) after daily inhalation of ovalbumin (OA) in sensitized guinea-pigs was investigated. Starting 3 weeks after sensitization (OA at 50 mg/kg s.c.+i.p.) guinea-pigs were exposed daily to 2% OA (10 min; under cover of 0.5 mg/kg mepyramine i.p. 15 min before OA) for 2 weeks. Concentration-response curves (CRCs) for inhaled ACh were performed 24 h after the last OA-challenge and 24 h after another single OA-inhalation 1 week later. CRCs for inhaled ACh were neither affected 24 h after the last OA challenge (daily for two weeks) nor 24 h after another OA-inhalation one week later. In contrast, bronchoalveolar lavage (BAL) from repeatedly OA- sensitized/-challenged guinea-pigs immediately after the last CRC showed a significant increase of total cell count by about tenfold and increases in eosinophils by about 20-fold, neutrophils by 30-fold, macrophages by about fivefold and lymphocytes by about tenfold (P < 0.05, multiple Wilcoxon-test). In contrast, markers of cell activation (EPO, MPO) were significantly decreased (P < 0.05). Methylprednisolone almost completely prevented these changes in increased cell numbers and decreased cell activation (vs OA contr., P < 0.05). The lack of increased airway hyperresponsiveness despite a massive inflammatory cell influx suggests other factors controlling airway responsiveness than inflammation.     

Processing/activation of caspases, -3 and -7 and -8 but not caspase-2, in the induction of apoptosis in B-chronic lymphocytic leukemia cells

Chlorambucil and prednisolone, two commonly used drugs in the treatment of chronic lymphocytic leukemia (CLL), induce apoptosis in CLL cells. We have investigated the involvement in this apoptotic cell death of caspases, which cleave critical cellular substrates thereby acting as the executioners of the apoptotic process. Induction of spontaneous or chlorambucil/prednisolone-induced apoptosis of freshly isolated B-CLL cells in culture resulted in the activation of the 'effector' caspases, -3 and -7, but generally not of caspase-2. Activation of caspases-3 and -7 was accompanied by the proteolysis of the DNA repair enzyme, poly (ADP-ribose) polymerase. Induction of apoptosis was also accompanied by the processing of caspase-8, the extent of which varied between patients. Induction of apoptosis and processing of all the caspases was inhibited by the cell permeable caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD.fmk). Our results demonstrate a key role for the activation and processing of caspases in the execution phase of apoptosis in CLL cells. Apoptosis of CLL cells resulted in the selective activation of some but not all caspases. Our results suggest that the dysregulation of apoptosis observed in CLL may be due to the signalling leading to the activation of caspases rather than a deletion of pro-caspases. High levels of caspase-8 in CLL cells in conjunction with low levels of CD95 receptor may offer new therapeutic opportunities for the treatment of CLL.     

Respiratory symptoms and bronchial responsiveness are related to dietary salt intake and urinary potassium excretion in male children

Six men were accidentally exposed to NO2 when they were changing a propeller using a gas burner in the poorly ventilated hold of a ship. All of them were admitted to hospital with shortness of breath and cough. Chest X-ray on admission revealed diffuse, patchy and infiltrative shadows, leading to the diagnosis of pulmonary edema in all five patients. Steroid therapy was effective and followed by a quick recovery in all patients. None developed third phase manifestations characterized pathologically by bronchiolitis obliterans.     

The association of respiratory symptoms and lung function with the use of gas for cooking. European Community Respiratory Health Survey

The association of respiratory symptoms and lung function with the use of gas for cooking was examined using data collected as part of the European Community Respiratory Health Survey, an international multicentre study. Associations between gas cooking and respiratory symptoms and respiratory function were assessed by logistic and multiple regression models. Tests for interaction were used to examine whether the effect of gas cooking varied between centres and, as there was evidence for this, the average effects were estimated using standard methods for random effects meta-analysis. Data from 5,561 males and 6,029 females living in 23 centres in 11 countries were analysed. There was no significant association found between respiratory symptoms and gas cooking in males. In females the association between some respiratory symptoms and gas cooking varied between centres with an overall positive association with "wheeze in the last 12 months" (odds ratio (OR) 1.24: 95% confidence interval (95% CI) 1.00-1.54) and "wheeze with breathlessness in the last 12 months" (OR 1.33: 95% CI 1.06-1.69). There was no evidence that atopy modified this association. Cooking with gas was associated with airways obstruction in both males and females although the differences failed to reach statistical significance. In some countries the use of gas for cooking is associated with respiratory symptoms suggestive of airways obstruction in females.     

Antigen-induced airway hyperresponsiveness is associated with infiltration of eosinophils in lung tissue, but not with bronchoalveolar lavage eosinophilia or neutrophilia

Hemimicropsia is a rare disorder of visual perception characterized by an apparent reduction of the size of objects when presented in one hemifield. We report two cases of hemimicropsia resulting from focal brain lesions. The first patient was an art teacher and could accurately depict his abnormal visual perception. He subsequently died and his brain was examined post mortem. In the second patient, micropsia was assessed by a quantified size comparison task. The size of a given object is normally perceived as constant across any spatial position. Hemimicropsia may thus be considered a limited violation of the size constancy principle. Behavioural and anatomical data are discussed in relation to the neural basis of visual object perception in humans.